TY - JOUR
T1 - Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death
AU - Garcia-Bermudez, Javier
AU - Baudrier, Lou
AU - Bayraktar, Erol Can
AU - Shen, Yihui
AU - La, Konnor
AU - Guarecuco, Rohiverth
AU - Yucel, Burcu
AU - Fiore, Danilo
AU - Tavora, Bernardo
AU - Freinkman, Elizaveta
AU - Chan, Sze Ham
AU - Lewis, Caroline
AU - Min, Wei
AU - Inghirami, Giorgio
AU - Sabatini, David M.
AU - Birsoy, Kıvanç
N1 - Funding Information:
Acknowledgements We thank all members of the Birsoy laboratory for helpful suggestions. We also thank R. Sordella for DD-Cas9 lentiviral plasmid, and R. Milne and J. Ersching for LDLR hybridoma cells. This research was supported by an EMBO long-term fellowship (EMBO ALTF 887-2016) to J.G.-B.; and by grants from the NIH (R01 CA103866 and R37 AI47389) and Department of Defense (W81XWH-07-0448) to D.M.S. AIRC Special Program in Clinical Molecular Oncology (10007), SCOR LLS and the Sandra and Edward Meyer Cancer Center PDTX Shared Resource supported G.I. D.M.S is an investigator of the HHMI and ACS Research Professor. K.B. was supported by K22 (1K22CA193660), DP2 (DP2 CA228042-01), Irma-Hirschl Trust Scholarship, Chapman-Perelman MMRF grant, AACR NextGen Grant, and is a Pew-Stewart, Searle, Sidney Kimmel and Basil O’Connor Scholar.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/3/7
Y1 - 2019/3/7
N2 - Cholesterol is essential for cells to grow and proliferate. Normal mammalian cells meet their need for cholesterol through its uptake or de novo synthesis1, but the extent to which cancer cells rely on each of these pathways remains poorly understood. Here, using a competitive proliferation assay on a pooled collection of DNA-barcoded cell lines, we identify a subset of cancer cells that is auxotrophic for cholesterol and thus highly dependent on its uptake. Through metabolic gene expression analysis, we pinpoint the loss of squalene monooxygenase expression as a cause of cholesterol auxotrophy, particularly in ALK+ anaplastic large cell lymphoma (ALCL) cell lines and primary tumours. Squalene monooxygenase catalyses the oxidation of squalene to 2,3-oxidosqualene in the cholesterol synthesis pathway and its loss results in accumulation of the upstream metabolite squalene, which is normally undetectable. In ALK+ ALCLs, squalene alters the cellular lipid profile and protects cancer cells from ferroptotic cell death, providing a growth advantage under conditions of oxidative stress and in tumour xenografts. Finally, a CRISPR-based genetic screen identified cholesterol uptake by the low-density lipoprotein receptor as essential for the growth of ALCL cells in culture and as patient-derived xenografts. This work reveals that the cholesterol auxotrophy of ALCLs is a targetable liability and, more broadly, that systematic approaches can be used to identify nutrient dependencies unique to individual cancer types.
AB - Cholesterol is essential for cells to grow and proliferate. Normal mammalian cells meet their need for cholesterol through its uptake or de novo synthesis1, but the extent to which cancer cells rely on each of these pathways remains poorly understood. Here, using a competitive proliferation assay on a pooled collection of DNA-barcoded cell lines, we identify a subset of cancer cells that is auxotrophic for cholesterol and thus highly dependent on its uptake. Through metabolic gene expression analysis, we pinpoint the loss of squalene monooxygenase expression as a cause of cholesterol auxotrophy, particularly in ALK+ anaplastic large cell lymphoma (ALCL) cell lines and primary tumours. Squalene monooxygenase catalyses the oxidation of squalene to 2,3-oxidosqualene in the cholesterol synthesis pathway and its loss results in accumulation of the upstream metabolite squalene, which is normally undetectable. In ALK+ ALCLs, squalene alters the cellular lipid profile and protects cancer cells from ferroptotic cell death, providing a growth advantage under conditions of oxidative stress and in tumour xenografts. Finally, a CRISPR-based genetic screen identified cholesterol uptake by the low-density lipoprotein receptor as essential for the growth of ALCL cells in culture and as patient-derived xenografts. This work reveals that the cholesterol auxotrophy of ALCLs is a targetable liability and, more broadly, that systematic approaches can be used to identify nutrient dependencies unique to individual cancer types.
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UR - http://www.scopus.com/inward/citedby.url?scp=85062374045&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-0945-5
DO - 10.1038/s41586-019-0945-5
M3 - Article
C2 - 30760928
AN - SCOPUS:85062374045
VL - 567
SP - 118
EP - 122
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7746
ER -